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A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection

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Science Translational Medicine  06 Dec 2017:
Vol. 9, Issue 419, eaan8848
DOI: 10.1126/scitranslmed.aan8848
  • Fig. 1. Trial design.

    (A) Consolidated Standards of Reporting Trials (CONSORT) flow diagram for the trial. CONSORT diagram delineates the study enrollment of 31 subjects who underwent randomization to the placebo or vaccine groups. (B) Schematics of study design. Blue arrows indicate time of HIV plasmid DNA (pDNA)/IL-12 or placebo administration. Red arrows indicate time of HIV rVSV gag or placebo administration. ART, antiretroviral therapy.

  • Fig. 2. Effect of therapeutic vaccination on immunologic and virologic parameters.

    (A) Levels of longitudinal plasma viremia of the study participants in the vaccine (n = 14) and placebo (n = 15) groups during the analytical treatment interruption (ATI) phase are shown. (B) Levels of plasma viremia in the vaccine and placebo groups were compared using the Wilcoxon rank sum test at the end of treatment interruption periods to determine the antiviral efficacy of the therapeutic vaccine regimen. Gray horizontal bars indicate geometric mean values. The limit of detection of plasma viremia (gray dotted line) was 40 copies/ml of HIV RNA. (C) Proportion of subjects remaining off antiretroviral therapy (ART) during the 16-week treatment interruption phase of the study. The horizontal axis gives the time in days since stopping ART. One subject in the placebo group broke protocol and prematurely restarted ART before day 112 (the end of the treatment interruption phase); data for this subject were censored at day 72. P value was calculated by exact log rank. Kaplan-Meier analysis of suppression of plasma viremia after cessation of ART is also shown. Duration of plasma viremia under 40 and 400 copies of HIV RNA/ml after discontinuation of ART was compared between the groups. (D) Proportions of visits with plasma viremia of <400 copies/ml. Per-subject proportions of study visits with plasma viremia of <400 copies/ml after discontinuation of ART were compared between the vaccine and placebo groups using the Wilcoxon rank sum test. (E) CD4+ T cell counts of study subjects before (baseline), at the end of the treatment interruption phase (ATI), and at the end of study (EOS). Vaccine and placebo arms were compared using a mixed model after log transformation of CD4+ T cell counts. Fixed effects included arm, time (treated as categorical), and arm-by-time interaction. The P value was based on the arm-by-time interaction.

  • Fig. 3. Relationship between therapeutic vaccination, timing of plasma viral rebound, and outcome of treatment interruption with HIV reservoirs.

    (A) Effect of therapeutic vaccination on HIV reservoirs. Levels of HIV DNA, cell-associated HIV RNA, and replication-competent virus in the CD4+ T cells of study subjects in the vaccine and placebo groups were determined during the vaccination period before discontinuation of ART. Vaccine and placebo arms were compared using a mixed model with the same fixed effects as in Fig. 2E. TBP, TATA box–binding protein. (B) Relationship between the size of HIV reservoirs and timing of plasma viral rebound after cessation of ART. The impact of the size of HIV reservoirs (HIV DNA, cell-associated HIV RNA, and replication-competent virus in CD4+ T cells) on the timing of plasma viral rebound of >40 copies/ml after discontinuation of ART was examined in all study participants as a whole using the Spearman rank correlation coefficient. (C) Relationship between the size of HIV reservoirs and levels of plasma viremia after discontinuation of ART. The effect of the size of HIV reservoirs (HIV DNA, cell-associated HIV RNA, and replication-competent virus in CD4+ T cells) on the capacity and the level of control of plasma viremia at the end of treatment interruption periods was examined in all study participants as a whole using the Spearman rank correlation coefficient.

  • Table 1. Baseline characteristics of participants.
    CharacteristicPlacebo (n = 16)Vaccine (n = 14)Total (n = 30)
    Sex, no. (%)
      Male16 (100)14 (100)30 (100)
    Age, years
      Median (interquartile range)42 (32, 48)40 (44, 26)41.5 (46, 31)
      Range24–6521–6021–65
    Inclusion criteria met*, no. (%)
      Acute infection6 (38)3 (21)9 (30)
      Early infection10 (62)11 (78)21 (70)
    Reported seroconversion illness, no. (%)9 (56)9 (64)18 (60)
    Time between HIV diagnosis and start of ART, days
      Median (interquartile range)25 (8, 53)28 (3, 73)28 (18, 46)
      Range0–883–730–88
    Duration of HIV suppression on ART at study entry, years
      Median (interquartile range)4.8 (2.7, 10.3)2 (1.7, 3.2)3 (1.8, 6.6)
      Range1.1–131.2–191.1–19
    CD4+ count, cells/mm3 at study entry
      Median (interquartile range)758 (596, 1165)726 (610, 942)749 (604, 942)
      Range501–2162363–1017363–2162
    Viral clade
      B151227
      A/G022
      Unknown101

    *See Materials and Methods for acute and early infection inclusion criteria.

    P = 0.0526.

    • Table 2. Effect of therapeutic vaccination on immunologic responses to HIV.

      The frequency of study subjects whose CD3+CD4+ and CD3+CD8+ T cells responded to overlapping HIV peptides during the vaccination phase before treatment interruption. Changes in the frequency of cells expressing intracellular cytokines upon peptide stimulation over baseline were determined as described in Materials and Methods. PTEg, global potential T cell epitopes.

      Peptide
      pool
      Number (percentage) of responders to HIV antigens
      CD3+CD4+ T cellsCD3+CD8+ T cells
      Vaccine
      group
      Placebo
      group
      Vaccine
      group
      Placebo
      group
      Env 1 PTEg4/12 (33%)0/13 (0%)5/13 (38%)3/13 (23%)
      Env 2 PTEg4/13 (31%)0/13 (0%)2/13 (15%)0/13 (0%)
      Gag 1 PTEg7/13 (54%)0/13 (0%)3/13 (23%)0/13 (0%)
      Gag 2 PTEg5/13 (38%)2/13 (15%)1/13 (8%)0/13 (0%)
      Nef PTEg0/13 (0%)1/13 (8%)1/13 (8%)0/13 (0%)
      Pol 1 PTEg2/13 (15%)0/13 (0%)0/13 (0%)1/13 (8%)
      Pol 2 PTEg3/13 (23%)1/13 (8%)0/13 (0%)1/13 (8%)

    Supplementary Materials

    • www.sciencetranslationalmedicine.org/cgi/content/full/9/419/eaan8848/DC1

      Fig. S1. Plasma viremia of individual study subjects after discontinuation of ART.

      Fig. S2. Gating strategy for ICS by flow cytometry.

      Fig. S3. Kinetics of HIV-specific T cell responses and immune parameters in placebo and vaccine recipients.

      Fig. S4. Detection of anti-VSV antibody in study subjects who received therapeutic vaccines.

      Table S1. Vaccine-related AEs.

      S2. Primary data.

    • Supplementary Material for:

      A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection

      Michael C. Sneller, J. Shawn Justement, Kathleen R. Gittens, Mary E. Petrone, Katherine E. Clarridge, Michael A. Proschan, Richard Kwan, Victoria Shi, Jana Blazkova, Eric W. Refsland, Daryl E. Morris, Kristen W. Cohen, M. Juliana McElrath, Rong Xu, Michael A. Egan, John H. Eldridge, Erika Benko, Colin Kovacs, Susan Moir, Tae-Wook Chun,* Anthony S. Fauci

      *Corresponding author. Email: twchun{at}nih.gov

      Published 6 December 2017, Sci. Transl. Med. 9, eaan8848 (2017)
      DOI: 10.1126/scitranslmed.aaan8848

      This PDF file includes:

      • Fig. S1. Plasma viremia of individual study subjects after discontinuation of ART.
      • Fig. S2. Gating strategy for ICS by flow cytometry.
      • Fig. S3. Kinetics of HIV-specific T cell responses and immune parameters in placebo and vaccine recipients.
      • Fig. S4. Detection of anti-VSV antibody in study subjects who received therapeutic vaccines.
      • Table S1. Vaccine-related AEs.

      [Download PDF]

      Other Supplementary Material for this manuscript includes the following:

      • Table S2. (Microsoft Excel format). Primary data.